A transdermal drug delivery system is a type of drug delivery system that delivers drugs through the skin, and is characterized by long duration and its ability to contain a large amount of drugs compared to other drug delivery systems such as oral administration agents, inhalants, injections, and the like. A first-generation transdermal drug delivery system is a patch-type product including a smoking cessation patch (nicotine patch), an inflammation treatment patch (Ketotop), a sickness patch (Kimite), a pain relief patch (pas), and the like, and is in a patch form with a drug applied thereon. This system operates under a principle that a drug acts locally or systemically through the skin, but it has a limitation in delivery in that only small-molecular-weight compounds and very few hydrophobic drugs can pass through the skin barrier, and it is disadvantageous in that, even though passing through the skin barrier, the drug is not effective in a lesion while maintaining an appropriate amount thereof.
To address the problems of a patch, which is a first-generation transdermal drug delivery system, e.g., in terms of passing through the skin barrier and efficacy, a variety of techniques have been developed. Electroporation is a technique for applying an electric field to a cell membrane to temporarily penetrate an external substance into a cell or tissue, and is applied as a means for injecting, into cells, compounds ranging from a low-molecular-weight compound such as an anticancer agent to a high-molecular-weight compound such as DNA.
However, the electroporation system is inconvenient when used, and thus it is difficult for ordinary people to easily use this system. An ultrasound technology is a technique that non-invasively increases permeation efficiency by applying an electric field to the cell membrane through ultrasound, and is used to inject a large amount of drugs or genes into cells and tissues and is also applied as an imaging method for aid in understanding of skin tissues when injecting a drug. However, since accurate understanding of the intracellular delivery mechanism through the ultrasound technology is still lacking, much research is needed to apply the ultrasound technology as a practical transdermal drug delivery technology. A jet injection technology is a technique that does not use an injection needle and non-invasively delivers a drug in a powder or liquid form through the skin by gas pressure. Since first developed, various drugs such as vaccines, toxoids, DNA, and the like have been applied through this technology, and this technology has flexible drug applicability. However, unlike other transdermal drug delivery technologies, the jet injection technology has a problem in that a drug tends to spread widely rather than locally, and thus cannot be delivered intensively to the dermis, and shows skin side effects such as blisters, erythema, hardening, hematoma, and the like.
A microneedle is a micro-level small syringe that can overcome pain trauma infection resistance, which is a disadvantage of existing syringes, and deliver drugs and physiologically active substances with high efficiency. The microneedle is as safe as the first-generation patch, causes no pain, and can deliver an active ingredient rapidly and efficiently like injections. Biodegradable microneedles, which are one type of microneedles, load a physiologically active substance in a biodegradable polymer matrix and deliver the physiologically active substance using the mechanism of the biodegradable matrix when penetrating the skin. A variety of first-generation transdermal drug delivery systems, such as electroporation, ultrasound, jet injection, and the like, require specialist procedures, while microneedles are a self-administrative system.
Drug delivery of biodegradable microneedles is mostly based on the first-generation patch agent, in which a biodegradable microneedle structure including a drug is formed on a patch-type adhesive. For efficient drug delivery, an adhesive patch needs to be attached to the skin for about 1 hour to about 2 hours, which is the point in time when the biodegradable polymer matrix is completely dissolved, resulting in side effects such as erythema, inflammation, allergic reactions, and the like. Recent research shows that, when a biodegradable microneedle patch is applied to the skin, the microneedles do not completely penetrate into the skin, resulting in incomplete drug delivery efficiency (Ryan F. Donnelly et al. Journal of Controlled Release 147:333-341(2010)).
Examples of existing biodegradable microneedle fabrication methods include micro-molding (Jung-Hwan Park et al., Biodegradable polymer microneedles: Fabrication, mechanics and transdermal drug delivery, Journal of Controlled Release 104:51-66(2005)), drawing lithography (Kwang Lee and Hyungil Jung, Drawing lithography for microneedles: A review of fundamentals and biomedical applications, Biomaterials 33:7309-7326(2012)), droplet airborne blasting (Korean Patent Application No. 1136738), a method in which centrifugal force is used (Korean Patent Application No. 2013-0050462), and a method in which negative pressure is used (Korean Patent Application No. 2013-0019247), and all the manufacturing processes necessarily require mixing of a polymer with a drug. It is impossible to quantitatively load a drug due to the loss of a structure, occurring in a process of post-molding into a microneedle form using the polymer including a drug mixed therewith, and the amount of drug in the microneedle fabricated after molding should be subsequently evaluated. In addition, the microneedle is manufactured by a molding method using viscosity of the polymer, and thus the amount of drug that can be loaded in a patch of microneedles ranges only from several tens of micrograms to several hundreds of micrograms.
Due to mixing of a polymer with a drug during fabrication of microneedles, the polymer and the drug interact with each other, resulting in a drastic decrease in activity of the drug. The microneedle molding process necessarily requires evaporation of a solvent in the polymer, and, in this process, the structure of a drug (vaccine, hormone, antibody, and the like) of a polymer substance is modified and thus the drug cannot be used in the microneedle as a drug vehicle and, therefore, must be accompanied by a structural stabilizer such as sucrose, maltose, galactose, or the like.
To compensate for the drawbacks through polymer-drug intermixing, a technique for directly percutaneously delivering a powder-type drug was developed in the U.S.A. (Dexiang Chen et al., Nature Medicine 6:1187-190(2000)). The activity of various powdered drugs such as insulin, vaccine, and the like was tested. However, a separate device designed for high-pressure dispensing is needed to percutaneously deliver a powder-type drug, a gas should be refilled after being dispensed once, and the particle size of a sprayable powered drug is limited.
Throughout the present specification, many papers and patent documents are referred to and citations thereof are shown. The disclosures of the cited papers and patent documents are incorporated herein by reference in their entirety, and thus the level of the art to which the present invention pertains and the contents of the present invention will be explained more clearly.